Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses.
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Berry DC, Jin H, Majumdar A, Noy N
Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses.
Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4340-5. doi: 10.1073/pnas.1011115108. Epub 2011 Feb 23.
- PubMed ID
- 21368206 [ View in PubMed]
- Abstract
It currently is believed that vitamin A, retinol, functions through active metabolites: the visual chromophore 11-cis-retinal, and retinoic acids, which regulate gene transcription. Retinol circulates in blood bound to retinol-binding protein (RBP) and is transported into cells by a membrane protein termed "stimulated by retinoic acid 6" (STRA6). We show here that STRA6 not only is a vitamin A transporter but also is a cell-surface signaling receptor activated by the RBP-retinol complex. Association of RBP-retinol with STRA6 triggers tyrosine phosphorylation, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. The RBP-retinol/STRA6/JAK2/STAT5 signaling cascade induces the expression of STAT target genes, including suppressor of cytokine signaling 3 (SOCS3), which inhibits insulin signaling, and peroxisome proliferator-activated receptor gamma (PPARgamma), which enhances lipid accumulation. These observations establish that the parental vitamin A molecule is a transcriptional regulator in its own right, reveal that the scope of biological functions of the vitamin is broader than previously suspected, and provide a rationale for understanding how RBP and retinol regulate energy homeostasis and insulin responses.